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Study Finds Metastatic Prostate Cancer May Benefit From Precision Medicine Approach
Feb 29, 2016 | a GenomeWeb staff reporter
NEW YORK (GenomeWeb) – Metastatic prostate cancer may benefit from a precision medicine approach, according to a new study from Fred Hutchinson Cancer Research Center researchers.
As they reported today in Nature Medicine, the researchers used a range of genomic tools to analyze multiple tumors from more than 60 men with disseminated prostate cancer. From this, they found that an analysis of one metastatic tumor from a patient could capture the major oncogenic drivers present in all of that patient's disseminated tumors.
"If you look in multiple metastases within a given patient, they're actually very, very similar," senior author and Fred Hutch researcher Peter Nelson said in a statement. "They're not identical, but in terms of the key features of a cancer that would inform how best to treat that cancer, we can feel generally confident, at least with prostate carcinoma, that if you did sample a single tumor, you could make clinical decisions based on what you find."
Metastatic prostate cancer accounts for more than 27,000 deaths each year in the US, the researchers noted, and the most common way of treating it — suppressing circulating testosterone and thus the androgen signaling program — hasn't changed in 50 years.
Using a combination of whole-exome sequencing, array comparative genomic hybridization, and RNA transcript profiling, Nelson and his colleagues examined 176 primary or metastatic prostate cancer tumors taken at autopsy from 63 men. From this, they uncovered recurrent mutations in AR, ERG, TP53, RB1, SPOP, CHD1, and ZBTB16 — all genes previously linked to metastatic prostate cancer. They also noted a recurrent change in FOXA2.
Overall, the researchers found that the lethal prostate cancers harbored a set of changes that were found across all samples as well as ones that were unique to the particular individual. Two-thirds of the men had amplifications or mutations of the AR gene, a change that isn't common among untreated primary tumors. Despite having undergone treatment to suppress AR expression, many of the patients' tumors still had robust AR activity.
Within an individual's tumors, the researchers noted limited genetic diversity.
For instance, Nelson and his colleagues found that one patient exhibited AR copy gain, high AR activity, and a p53 mutation, but lacked a v-ets avian erythroblastosis virus E26 oncogene homolog rearrangement. Four other tumors from this patient showed the same characteristics. In addition, they noted that the tumors shared a subset of nonsynonymous single nucleotide variants, though each did have a few private mutations.
This and other findings suggested to the researchers that genomic analysis of one metastatic tumor might capture the range of alterations seen in that individual's other tumors, and suggest possible treatments.
"Although the analysis of a single metastatic tumor site clearly does underestimate the total burden of molecular aberrations found in the totality of all metastases, most drivers and actionable features are either represented as common roots across all tumors or result from convergent evolution…," Nelson and his colleagues wrote in their paper. "Although there are exceptions, these findings suggest that clinical decision-making on the basis of a biopsy from a sin